Melanin-concentrating hormone (MCH) mediates a variety of neurological functions including appetite and energy expenditure. The discovery of MCH receptors in peripheral tissues such as adipose tissue and pancreatic beta cells broadens the potential impact of this hormone on the whole-body response to food. Many cells desensitize following an initial round of hormone exposure to prevent over-stimulation of a particular signaling pathway. This desensitization typically involves receptor phosphorylation followed by [unreadable]-arrestin recruitment and physical removal of the receptor from the plasma membrane via clathrin- mediated endocytosis. Alternatively, non-clathrin vesicles, such as caveolae, participate in agonist- mediated receptor endocytosis. Our lab's preliminary data, in conjunction with studies published by other labs, suggest that both desensitizing pathways participate in the regulation of MCH signaling, however the molecular intricacies of each have yet to be worked out. This project specifically 1) characterizes the localization of MCHR1 to caveolae and establishes its impact of receptor function;2) elucidates the involvement of agonist-induced phosphorylation and [unreadable]-arrestin-2 recruitment in MCHR1 desensitization;and 3) maps the post-endocytic trafficking route of agonist-occupied MCHR1. The results from this work will impact the fields of receptor biology and appetite physiology. The experiments described are designed to enable the participation of undergraduate and Master's research students choosing to engage in biomedical research training opportunities at our institution. PUBLIC HEALTH RELEVANCE: Melanin-concentrating hormone regulates a wide range of physiological functions, the most widely known being appetite and energy expenditure. The experiments proposed herein are designed to provide us with detailed information regarding how MCH signaling is turned off, or desensitized, by cells. Abnormal MCH receptor desensitization mechanisms could result in excess appetite signaling and an obese phenotype. As we gain knowledge regarding the molecular basis for MCH signaling, novel pharmacological targets may be identified, and new medications may be developed in our fight against obesity.